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Opioids Can Heighten Pain Through an Immune System Protein

A new study shows how opioids can actually increase pain. The relevance of the findings to people with persistent pain remains uncertain. Image credit: pixelrobot/123RF Stock Photo.

Opioids provide powerful relief from pain, but they have many dangerous side effects, such as physical dependence and tolerance. This requires ever-increasing doses to achieve the same pain relief.

But a lesser-known side effect is called opioid-induced hyperalgesia (OIH). Here, opioids actually make people and animals more sensitive to pain, not less. Researchers led by Jon Levine at the University of California, San Francisco, are now reporting new discoveries about the paradoxical phenomenon of OIH, in studies using rats.

They show that opioids at both high and low doses cause peripheral sensory neurons to send even stronger electrical signals. (Peripheral sensory neurons generate and relay electrical signals in response to potentially painful events—think of a hand touching a hot stove, or a foot stepping on a nail—from the body into the spinal cord).

And, while OIH generally occurs with the use of opioids over time, the new work shows that the drugs can heighten pain sensitivity after even a single dose of morphine.

The investigators also found that both OIH (and another phenomenon called hyperalgesic priming; see below) by a low dose of morphine depended on an immune system protein called toll-like receptor 4 (TLR4), rather than on the opioid receptor (a protein that, when activated by opioids, eases pain).

“I’m excited by the work,” said Mark Hutchinson, University of Adelaide, Australia, who studies the role of the immune system in chronic pain but was not involved in the current study. “Clearly they’ve done some beautiful pharmacology here,” referring to the studies of high and low doses of opioids.

And, according to Hutchinson, the research represents a favorable shift in thinking about how opioids work. “I take a lot of encouragement from the fact that there is discussion beyond just opioid receptors.”

Prime time
The UCSF team has long aimed to understand the mechanisms underlying chronic pain—that is, what it is that happens at a cellular and molecular level in the nervous system to produce pain. But they realized that the common approach of defining pain based on how long symptoms last was not very helpful when trying to do so.

“Chronic pain is customarily defined as pain that lasts longer than some period of time, be it three months, six months, a year. As researchers trying to understand its mechanisms, that didn’t make any sense to us. So we wanted to make a model to study how acute pain becomes chronic from a mechanistic point of view—where time itself was not a central tenet to the diagnosis of chronic pain,” said Levine.

With that in mind, Levine and colleagues previously developed a model of chronic pain they refer to as “hyperalgesic priming.” With that model, they are trying to see if a previous experimental injury or insult of some sort, such as nerve damage, makes animals even more sensitive to later injection of a substance that causes pain. In this case, the researchers used an inflammatory substance called prostaglandin E2 (PGE2).

“Animals injected with PGE2 had hyperalgesia [increased sensitivity to pain] that lasted less than an hour,” Levine explained. “But when we took an animal that had peripheral neuropathy [nerve damage], prior inflammation or stress-induced pain, PGE2 injection caused tenderness that persisted for days.” In short, a prior insult or injury had “primed” the animals to become even more sensitive to PGE2.

What does this have to do with opioid drugs? It turns out that opioids taken before surgery can increase the risk of chronic pain. So the researchers thought that opioids might also be causing hyperalgesic priming.

The new research also builds on a recent study from the same group. That previous research found that a single injection of a very low dose of morphine increased pain sensitivity in rats.

“We didn’t have any idea that would happen,” said first author of the new work, Dioneia Araldi, also of UCSF. “It was very surprising.”

“There is a novelty to it,” Hutchinson said of the increased pain sensitivity resulting from a low dose of an opioid.” And yet, he added, “nothing surprises me anymore” when it comes to understanding how opioids work, which studies have revealed to be incredibly complex.

Which protein?
The researchers had also found that a low dose of morphine did not seem to work through opioid receptors. So, in the new study, the researchers tested whether low-dose opioids might cause OIH through TLR4. TLR4 is a well-known protein in the immune system that is involved in some other side effects of opioids, so it seemed like a good molecule to focus on.

The investigators used a genetic technique to reduce how much TLR4 rats had in the spinal cord. They found that these animals, when given a low dose of morphine, did not develop OIH. Hyperalgesic priming was also improved. These findings showed that TLR4 was necessary for the negative effects of opioids to occur.

But, similar experiments would show that a high dose of morphine did not depend on TLR4—only the low dose did. Instead, with high doses, priming, as well as relief from pain, depended on opioid receptors. These findings reveal that opioids work in complicated ways to produce their effects; no single explanation for how these drugs function will suffice.

What is the relevance to people with persistent pain who take opioids?
So what does this all mean for patients? Hutchinson said it’s not yet clear how the findings relate to the repeated oral doses of opioids that people typically take. But, he added, the work “paints more of that complexity to the story.”

How big of a problem is OIH for patients? Hutchinson said, “When I ask clinicians, do they believe in OIH, I think about 60 percent say, ‘I’ve never seen it,’ and 40 percent say, ‘maybe it does exist.’ Then you have the extremes of those populations: doctors who say, ‘it absolutely doesn’t exist,’ or ‘yes, I see it, and it’s a massive problem.’ That’s in the clinic.”

“Now, we definitely can see OIH in rodents, no doubt,” he added. “We learn more about the nuances of the fundamental science from these studies, and we’ll need to do more to see how it translates and how it’s relevant to the clinical population.”

However, Hutchinson said, the new study also raises the point that opioids are not a good solution for long-term pain management, and for some people they may be worse than for others. Each patient is unique, “so opioids are not always going to work the way we think and just create analgesia [pain relief].”

“If that’s the message that people take home,” Hutchinson continued “maybe they’ll be ready for these negative effects. I care about the person who is currently sitting in unremitting agony, and opioids are not necessarily the solution for that person, because maybe if they have a super-sensitive immune system, then they’re going to have more bad effects from opioids than good.”

Stephani Sutherland, PhD, is a neuroscientist and freelance journalist in Southern California. Follow her on Twitter @SutherlandPhD

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